Human T-lymphotropic virus type 1 (HTLV-I) is the etiologic agent for both, adult T-cell leukemia/lymphoma (ATLL) and a chronic myelopathy and is an important public health problem in the United States. In contrast to the muted transcription exhibited by the virus during persistent infections, virus replication is increased during neurologic disease states and is necessary for cell transformation. Limited information is known of specific host control mechanisms that regulate HTLV-I expression during activation of the host cell (CD4+ lymphocytes). Further research is needed to define the molecular details of how HTLV-I-infected T- lymphocytes regulate virus transcription when activated through physiologically relevant receptor pathways. The proposed research is based on the following HYPOTHESIS: Signal transduction initiated via the T-cell receptor/CD3 (TCR/CD3) complex and CD2 receptor promote the replication and leukemogenic potential of HTLV-I in infected T- lymphocytes. HTLV-I cell lines, as well as HTLV-I-infected normal lymphocytes during the course of transformation will be used to determine the influence of these receptor-mediated pathways at three sequential levels from cell membrane receptor-binding and generation of secondary cell signals through assessment of cellular proteins which bind viral promoter sequences. Following CD3 and CD2 receptor-mediated activation of HTLV-I-infected CD4+ T-lymphocytes, I postulate that the effects of second signals are mediated by specific cellular proteins which bind viral promoter sequences and enhance virus transcription. Therefore, the long term goal of the proposed research is to molecularly define how these receptor pathways determine the extent of viral replication and cell proliferation in the natural target cell of the virus (CD4+ T lymphocytes). The Specific Aims of the proposed research are threefold: 1) determine HTLV-I expression and cellular proliferation during CD3 and CD2 receptor-mediated activation of virus infected lymphocytes, 2) analyze the effect of cAMP and protein kinase C activators and inhibitors on HTLV-I expression during CD3 and CD2 receptor-mediated activation, 3) demonstrate that CD3 and CD2 receptor activated CD4+ lymphocytes produce specific cellular proteins which bind HTLV-I promoter sequences and facilitate HTLV-I transcription.